This project (Project 3 of a three project proposal entitled Structure based design of antibodies and vaccines responding to the RFA-AI-14-028 ?Modeling Immunity for Biodefense?) will develop computational methods to predict the epitope specificity of antibody immune responses to structural antigens, will develop computational methods to design structurally stable antigens with customized surfaces to enable focusing of antibody immune responses to preselected epitopes, and will test these methods by experiment, by assessing immune responses to designed model antigens. The primary model system will be the head domain of influenza hemagglutinin and the focus will be on the epitopes within and around the receptor binding site, but other model systems will include neutralizing epitopes of glycoproteins from dengue virus and ebola virus. To assist computational methods development, in vitro cell surface display methods will be employed to improve the properties of designed antigens, and those results will feed back to guide algorithmic improvements. Likewise, results from immunization studies will feed back to guide refinement of the methods. The project 3 specific aims are: (1) Develop and benchmark computational methods to predict epitope immuno-visibility (2) Develop computational methods to design structurally stable epitope-focused immunogens and experimentally test those methods by evaluating immune responses to designed model antigens (3) Develop computational methods to resurface immunogens to focus immune responses to preselected epitopes, and test those methods by evaluating immune responses to designed model antigens. .